    Patent Document 1: JP-A H04-295420    Patent Document 2: JP-A 2006-104193    Patent Document 3: JP-A H07-277729    Patent Document 4: JP-A 2005-270745    Patent Document 5: JP-A 2003-159696    Patent Document 6: JP-A 2003-210957    Patent Document 7: JP-A H06-227967    Patent Document 8: JP-A 2007-77061    Non-Patent Document 1: “Nanotechnology Handbook, Part I, Creation”, first edition, first print, 2003, published by Ohmsha Ltd. (Kandanishiki-cho 3-1, Chiyoda-ku, Tokyo, JP)
The nanotechnology attracts a great deal of attention as a scientific technology raising a new industrial revolution. Because a conventional substance can exhibit new functions by converting the substance into microparticles, the conversion of the substance into nanoparticles is an important theme in the whole industrial world, and the interest in the technology of conversion into nanoparticles is extremely increasing for advance of the nanotechnology. (Non-Patent Document 1) (Non-Patent Document 1)
Particularly with respect to substances intended to be ingested by the living body (biologically ingestible substances), such as foods, food additives, cosmetics and pharmaceutical preparations for drugs and medicines, microparticulation technology draws increasing attention, and particularly the microparticulation of drugs and medicines in pharmaceutical preparations is known to bring about improvements in solubility, that is, significant improvements in the degree of biological absorption, and is increasingly expected.
On the other hand, a long time for development and depletion of possible substances become problematic in creation of a new possible substance for drugs and medicines, and one of such causes is that the possible compound is poorly water-soluble so that a change in the structure of the compound may be necessary and thus the development may be increasingly delayed or deadlocked. Because possible compounds selected to be developed are low in solubility, there is also a problem that not only formulation of drugs and medicines but a toxicity test and evaluation of their dynamics cannot be advanced. However, some compounds are highly membrane-permeable even being low in solubility in water, and can be sufficiently absorbed after oral administration, so that when compounds are dropped in view of solubility only, promising compounds may be also left out. Accordingly, there is a desire to develop formulating technology for improving solubility and consequently for improving the degree of absorption into the living body.
It is reported that, in many cases, even a poorly water-soluble drug, when finely atomized, increases its surface area and increases the rate of dissolution, thereby increasing absorption into the living body. For example, the biological availability (BA) of an anti-endometriosis drug danazol was 5.1% when its commercial product (average particle diameter: 10 μm) was administered to a dog in the form of a suspension, while the BA of danazol was significantly increased to 82.3% when the drug was administered in the form of a nano-suspension having an average particle diameter of 169 nm (Int J. Pharm. 125, 1995, 91-97). When an anti-inflammatory agent naproxen was administered to a rat, its absorption was increased four times as much by atomizing its bulk powder of 20 to 30 μm into powder of 270 nm (Int J. Pharm 125, 1995, 309-313). Accordingly, when a poorly water-soluble drug can be formed successfully into nanoparticles, the absorptivity of the drug can be significantly improved.
Under this background, manufacturing technologies of atomizing (nano atomization) a drug have been desired, and for industrial application of such technologies, the establishment of a production method capable of stable mass production is one of the most important tasks in the application of nanotechnology to pharmaceuticals.
Generally, as a method for producing microparticles, there are: a break-down method (crushing method) of mechanically crushing and atomizing a bulk-state material to obtain microparticles; and a bottom-up method (developing method) of aggregating atoms and molecules thereby developing them into microparticles of suitable size.
As a crushing method, included are a mechanical crushing style of using a mill such as a ball mill, an attritor mill, a vibrator mill, a sand mill, a roller mill or a Cowles-type mixer, and another style of radiating femtosecond laser to solid particles such as a laser ablation. In the case of the mechanical crushing style, however, there is a fundamental limit to the degree of atomization by crushing, and there are problems of, for example, mix of impurities and lack of purity in products, since use of a crushing force generated by contacting a medium mill inevitably causes mix of broken particles of bead itself. Further, enormous energy is required, so that at present there is also a problem in energy costs. The laser ablation method is a process of utilizing a crushing force by strong light, and thus the possibility of photodecomposition at the molecular level cannot be denied. The substantial amount of production under the present situation is about 0.1 mg/h and cannot be said to be at an industrially practicable level.
Further, microparticles produced by the crushing method generate active sites easily on their fracture surfaces as a result of physical crushing, so that the crushed microparticles are aggregated again to easily form coarser aggregates than before crushing. Accordingly, the utility value of the product may be deteriorated, or anomalies such as increase of viscosity in the dispersion system as a whole may be caused, so that there are many problems in the crushing methods themselves.
Patent Document 1 describes a method of obtaining drug microparticles, specifically a method of obtaining particles of less than 250 nm by means of a mill such as a ball mill, an attritor mill, a vibrator mill, a sand mill, a roller mill or a Cowles-type mixer. As for mix of foreign materials due to, for example, abrasion of media, it is merely referred to therein as not causing unacceptable contamination, and a risk of mix of foreign materials may arise a critical problem for pharmaceutical preparations in which high qualities always are required.
Next, the bottom-up method used as a method of preparing microparticles is a method utilizing various reaction means such as chemical reaction, crystallization and sublimation, wherein a reaction is used in combination with a polymer dispersing method, a thermal decomposition method, a supercritical method or a sonication method, thereby aggregating atoms and molecules to form microparticles.
As reaction means, a reaction method using a batch reaction container as described in Patent Document 3 or a gaseous phase method using plasma in a high vacuum as described in Patent Document 4 is used in some cases. Further, a microreactor and a micro-flow path reactor as described in Patent Documents 5 and 6 is utilized in some cases.
In a batch system, controlling temperature in the batch is generally difficult, and so is conducting a uniform reaction. Further, the control of concentration in a completely uniform state is not feasible, and thus the control of reaction conditions is difficult. Moreover, the reaction time should be prolonged, and thus a uniform reaction hardly proceeds under the control of all reaction conditions.
In a gaseous phase method, the amount of nanoparticles formed per unit time is small, and a high-energy apparatus to evaporate materials is necessary, such as an electron beam, plasma, a laser and induction heating. Further, the yield is low, so a gaseous phase method cannot be said to be very suitable for mass production in view of production costs. Furthermore, it is a problem that the nanoparticles obtained by a gaseous phase method are readily aggregated and fused together while a size of the particles varies, since the particles are microparticles of a pure substance.
It has been attempted to use a microreactor or a micromixer known in microchemical processing in a method for producing the biologically ingestible minute microparticles described above. However, when the microparticles are produced by these methods, the methods are not applicable to all the reactions, since the micro-flow path is closed with high possibility by clogging of the flow path with bubbles and byproducts generated by the reaction, and the reactions are allowed to proceed fundamentally by molecular diffusion only. The microchemical process uses a scale-up method of increasing the number of reactors arranged in parallel, but a problem is that because the manufacturing ability of one reactor is small, and scaling up in a large volume is not practical, and the respective reactors are difficult to be supplied with the same performance, thus failing to provide uniform products. When the reaction solution is highly viscous or the reaction causes increasing viscosity, very high pressure is necessary for passing of the solution through a minute flow path, so it concerns that a usable pump is limited, and leakage of the solution from an apparatus cannot cease due to the high pressure.
Particularly in the case of pharmaceutical preparations, high qualities are definitely required. Strongly desired are physicochemical qualities such as a crystal form or a crystal particle size, and basic qualities of having mixing of impurities and, further, insoluble microparticles, in the pharmaceutical preparations, so superb technologies of production meeting such requirements for qualities are required. However, substances produced in the chemical industry and produced as foods and pharmaceutical preparations often contain aggregates of fine crystals, and those with a mother liquid and impurities in crystals. Also, when atomization is done with a crushing device using media, mix of a media-derived foreign material is inevitable. From now on, consciousness of environmental issues and saving of resources and energy is necessary, thus including this, there are many problems to be resolved. Further in the process for producing biologically ingestible microparticles, mix of a foreign material and growth of bacteria in the process may cause a problem too, so the proposal of a production method capable of providing biologically ingestible microparticles in a safer and more inexpensive way by reducing production time is required.
Some poorly water-soluble drugs are soluble not only in organic solvents but also in acidic or alkaline solutions, but many of the drugs are known to be poor in stability of compounds in aqueous solutions in which they have been dissolved. For example, pirenoxine is hydrolyzed when dissolved in an aqueous solution of pH 6 or higher. Accordingly, many of pirenoxine eye drops commercially available should, just before use, be dissolved in an attached solvent and be prepared.
An aqueous suspension having a poorly water-soluble drug suspended therein is known too. However, the diameter of drug particles in aqueous suspended eye drops commercially available is several μm to several dozen μm, and thus these aqueous suspended eye drops are hardly subjected to filtering sterilization. For assuring the sterility of the preparations, it is necessary that sterilization such as final high-pressure steam sterilization or dry heat sterilization of the main raw material be done, and the whole of the production process thereafter be conducted by an aseptic operation. However, it is known that, when the final high-pressure steam sterilization is conducted, in a state from large to small particles mixed in it, small particles dissolve and disappear, while larger particles further grow (Ostwald ripening). In a sterilizing operation involving intense changes of the temperature, the particles further become coarser and coarser. During sterilization, a surface modifier/particle-solving agent is separated, which is accompanied by coarsened particles, and thus it is difficult to maintain dispersibility (JP-A H06-227967/Patent Document 7). When the dry heat sterilization of the main raw material is conducted, the thermal denaturation, adhesion and strong aggregation of the main raw material are caused, and thus mechanical crushing and dispersion treatment for a longer time are necessary, and as a result, an aseptic operation for a long time is required. In the case of the production method involving such aseptic operations, it costs for the aseptic facilities and operations, and aspects of production such as workability and of quality assurance such as maintenance of asepsis matter.
As an aqueous suspension of pirenoxine, a method capable of filtering sterilization and providing eye drops is shown in which pirenoxine is ultrafinely atomized by mechanical crushing to provide inexpensive eye drops (JP-A 2007-77061/Patent Document 8). However, the conventional mechanical production method requires a long time in atomization and suffers from problems such as productivity and increasing burden of costs due to high processing energy and complexity of the process. Further, many of atomizing machines use media, which indicates mix of media as foreign material and difficulty in acquisition of uniform particles and easy aggregation. It is also noted that coarse particles act as cores to promote aggregation.
Meanwhile, the fact that atomization of pirenoxine can improve osmotic properties to corneas and, in the form of an aqueous suspension, improving stability to light is known, and the same effect can be expected for other eye drops.
In the method for atomizing a pharmaceutical composition, particularly in the case of a poorly water-soluble drug, there is a method of improving solubility such as a pH regulating method, an organic solvent method, a micelle method, a complex method, a microemulsion method, and a microparticulation method. The methods other than the microparticulation method depend on physical properties of individual drugs and are thus not always applicable to every drug. The microparticulation method of crushing by a mechanical means can be applied widely to drugs, but there are problems such as easy aggregation, difficulty in acquisition of uniform particles, and mix of impurities in the crushing process.
The method of atomizing a drug includes a dry crushing method, a wet crushing method, a crystallization method, and so on. Generally, a pharmaceutical preparation is heat-labile, so that in the dry crushing method, there are problems due to heat generation during crushing process such as conversion into an amorphous compound, and occurrence of dust. The wet crushing method also suffers from problems such as a long processing time, and difficulty in regulating the diameter of attained particles. Further, use of media inevitably causes mix of a foreign material attributable to abrasion of the media, and the mixed foreign material is difficult to be isolated, thus making the resulting particles unusable in products requiring high purity.
In most cases, it takes long time for the wet crushing as described above to process, so that bacteria may grow over the time. In addition, a great burden of costs out of high processing energy and complexity of the process is concerned.
The method for producing drug microparticles includes a method of dissolving a compound in a solvent and then mixing the solution with a new solvent to separate crystals, and a method of dissolving a compound in a solvent by pH regulation and then changing the pH with an acid or an alkali to separate crystals. In such reaction methods, two liquids have been mixed usually by means of a dynamic mixing apparatus having a movable part in its mixing area, for example, a stirring and mixing apparatus having an impeller. It should be careful when such a mixing apparatus is used to process a compound having an extremely high rate of crystal growth. If it takes a long time to mix a solution of such a compound with a new solvent, separation of crystals is initiated in its solution in a state of nonuniform concentration, then particles having broad particle size distribution/particle diameter distribution, and coarse particles, depending on growth of crystals, are mixed, resulting in not obtaining the objective crystals having sharp particle size distribution/particle diameter distribution. There is also a method of separating microparticles by allowing a solution to be in contact with abase having protrusions, which are hardly different from each other, at density of at least 100 protrusions per square centimeter on the surface thereof (JP-A 2006-104193/Patent Document 2), but there still are many to be solved such as an amount of production.
It has been desired to provide stable and dispersible drug particles in nanomicron size, in which particle diameters are easily regulated; aggregation or precipitation after aggregation is unlikely to occur; other than main drugs, fewer additives such as surfactant and stabilizer are contained; and redispersibility is excellent. In addition, it has been strongly requested to provide a pharmaceutical composition, in which no contamination due to mechanical abrasion and the like happens; safety and stability are securely maintained; and bioavailability is excellent.